The broad objective of this new application is to advance our understanding of the pathophysiological mechanisms of human Cardiorenal Syndrome (CRS) with a specific emphasis upon the biological interaction between diuretic therapy, the renin-angiotensin-aldosterone-system (RAAS) and cyclic 3_- 5_-guanosine monophosphate (cGMP) pathway. Renal dysfunction is a common and progressive complication of chronic heart failure (CHF) and despite growing recognition of the frequent presentation of combined cardiac and renal dysfunction, or CRS, its underlying pathophysiology is not well understood, with a lack of consensus as to its appropriate management. The CRS can be classified into 2 broad categories: 1) patients with compensated CHF and impaired renal function;and 2) patients with decompensated CHF and worsening renal function. Diuretics are effective and necessary to relieve congestion in CHF however recent reports have suggested potential deleterious effects on the progression of CHF. We demonstrated that angiotensin II receptor (AT1) blockade prevented the detrimental renal effects of diuretics. Cyclic GMP (cGMP) is the second messenger of both the natriuretic peptide (NP) system and the nitric oxide system (NO). Both of these humoral systems are important in balancing the vasocontricting and sodium retaining hormones such as the angiotensin II to preserve renal function in CHF. To address these issues related to human CRS, we will pursue human studies taking advantage of the extensive clinical facilities, patient populations and our NIH funded General Clinical Research Center (GCRC) at the Mayo Clinic, which makes our proposed research highly feasible and of significant clinical importance. Our Specific Aims are as follows: Aim 1: To define the effects of decreasing the furosemide dose on cardiorenal and humoral function in humans with compensated CHF and renal dysfunction and also in humans with compensated CHF without renal dysfunction. Secondly, to define the humoral activation in both groups.. Aim 2: Define in humans with compensated CHF and renal dysfunction, the modulating actions of chronic AT1 receptor blockade on cardiorenal and humoral function as compared to increased ACE inhibition. Aim 3: Define in hospitalized decompensated CHF patients with CRS, the renal actions of low dose intravenous infusion of BNP in the presence and absence of acute PDE V inhibition in improving renal function. PUBLIC HEALTH RELEVANCE Chronic heart failure is a major health problem in the US and despite recent advances in the treatment, the outcome remains poor, especially in those patients with renal failure as well. This research should aid in addressing this health challenge.